Bone loss following bone fracture is a significant problem. Indeed, bone loss in combination with infection can lead to chronic osteomyelitis and non-union. Since the first report of incorporating antibiotics into bone cement in 1970, many hospitals have adopted the practice for prophylactic treatment during arthroplasty, as well as for arrest of chronic infections (McQueen M et al., Int Ortho 1987; 11:241-3; Fish DN et al., Am J Hosp Pharm 1992; 49: 2469-74; Hanssen AD and Osmon DR. Clin Ortho Rel Res 1999; 369(1): 124-38; Hanssen AD. J Arthroplas 2002; 17(4S1): 98-101).
The use of antibiotic-impregnated poly(methylmethacrylate) (PMMA) beads has also become widespread (Henry S L et al., Ortho Rev 1991; 20(3): 242-7; Popham G J et al., Ortho Rev 1991; 20(4): 331-7; Klemm KW. Clin Ortho Rel Res 1993; 295: 63-76), although in the case of infected non-unions or bony defects, this technology is typically used in two stage operations. In these cases, the defect or non-union site is debrided as needed and the infection treated by placement of antibiotic-impregnated PMMA beads into the defect site. In the second stage, the beads are removed approximately six weeks later and a graft is used to repair the bone defect. The graft can be animal derived, allogenic, or autologous, such as COLLAGRAFT® bone graft matrix, demineralized bone matrix, or bone from the iliac crest, respectively. This two-stage methodology has also been widely adopted (Ueng S W N et al., J Trauma 1996; 40(3): 345-50; Ueng S W N et al., J Trauma 1997;43(2):268-74; Chen C Y et al., J Trauma 1997; 43(5); 793-8; Swiontkowski M F et al., J Bone Joint Surg Br 1999; 81(B6):1 046-50).
In a logical progression of the technology, the two-stage method was soon followed by a one-stage procedure. In this technique, antibiotics are combined with the bone graft material in order to limit the intervention to a single surgery. Ideally, the resident antibiotic provides local delivery for prophylactic treatment of infection while the graft provides the environment to grow new bone. This methodology has also been widely adopted and used both with human autologous and bovine grafts as well as synthetic grafts (Chan Y S et al., J Trauma 1998; 45(4): 758-64; Chan Y S et al., J Trauma: Inj Inf Crit Care 2000; 48(2): 246-55; Winkler H et al., J Antimicrobial Chemo 2000; 46: 423-8; Sasaki S and Ishii Y., J Ortho Sci 1999; 4: 361-9; McKee MD et al., J Ortho Trauma 2002; 16(9); 622-7).
These approaches are not without their limitations. For example, the typical protocol for impregnation of antibiotic into PMMA is to heat the polymer to form a melt, then to mix powdered antibiotic into the liquid. The antibiotic must be heat stable to withstand the PMMA melt temperatures, which is often not the case so the number of potential antibiotics is limited. In addition, powdered antibiotic and liquid PMMA are not thermodynamically miscible; therefore the mixture is typically not homogeneous. This leads to uneven release of the antibiotic. Finally, the two-stage protocol subjects the patient to two surgeries and thereby, increased risk.
Similar limitations exist when impregnating graft materials with antibiotic. Typical graft materials are donor bone, demineralized bone matrix, or synthetic ceramic substitutes (e.g. hydroxyapatite), among others. These biomaterials are often not compatible with the antibiotic, and the resulting composite is non-homogeneous. Whether one employs impregnation into PMMA or a graft material, these methods, although clinically effective to some degree, are not controlled release systems and are by no means optimized for therapeutic dosing of antibiotics. They are osteoconductive, and in the case of autologous bone are certainly osteoinductive, but any approach that uses autologous bone subjects the patient to another wound. This increases risk to the patient and can lead to donor site morbidity, thereby compounding the original problem (Silber, J S et al., Spine 2003; 28(2): 134-9).
Obviously, healing bone defects is a challenging area of orthopaedic medicine. Current methods are not optimized for complete patient benefit. Ideally, bony defects should be healed with a graft material that provides both an osteoconductive and osteoinductive environment, and controlled, effective antibiotic treatment in a biomaterial that can be utilized in a single-stage operational protocol.
A recent review (Ludwig, S C et al., Eur Spine J 2000; 9(S1): S119-25) on the subject of bone graft substitutes listed the three most important elements of the ideal product as:                1. Osteoconductive in that it provides a scaffold conducive to vascular invasion, cell infiltration, and new bone formation;        2. Osteoinductive (i.e. capable of growth factor mediated differentiation of precursor cells into osteoblasts); and        3. Capable of delivering cells that will form new bone matrix.        
Any effective regeneration scheme must seek to optimize all three of these parameters in order to recapitulate functional bone. Accordingly, there is a continuing need for new compositions useful as bone graft materials.